Inhibitors and activators for myotoxic phospholipase A2-like toxins from snake venoms - A structural overview.

Snakebite envenomations result in acute and chronic physical and psychological health effects on their victims, leading to a substantial socio-economic burden in tropical and subtropical countries. Local necrosis is one of the serious effects caused by envenomation, primarily induced by snake venoms from the Viperidae family through the direct action of components collectively denominated as myotoxins, including the phopholipase A2-like (PLA2-like) toxins. Considering the limitations of antivenoms in preventing the rapid development of local tissue damage caused by envenomation, the use of small molecule therapeutics has been suggested as potential first-aid treatments or as adjuvants to antivenom therapy. In this review, we provide an overview of the structural interactions of molecules exhibiting inhibitory activity toward PLA2-like toxins. Additionally, we discuss the implications for the myotoxic mechanism of PLA2-like toxins and the molecules involved in their activation, highlighting key differences between activators and inhibitors. Finally, we integrate all these results to propose a classification of inhibitors into three different classes and five sub-classes. Taking into account the structural and affinity information, we compare the different inhibitors/ligands to gain a deeper understanding of the structural basis for the effective inhibition of PLA2-like toxins. By offering these insights, we aim to contribute to the search for new and efficient inhibitor molecules to complement and improve current therapy by conventional antivenoms.

BmajPLA(2)-II, a basic Lys49-phospholipase A(2) homologue from Bothrops marajoensis snake venom with parasiticidal potential

Snake venoms contain various proteins, especially phospholipases A(2) (PLA(2)s), which present potential applications in diverse areas of health and medicine. In this study, a new basic PLA(2) from Bothrops marajoensis with parasiticidal activity was purified and characterized biochemically and biologically. B. marajoensis venom was fractionated through cation exchange followed by reverse phase chromatographies. The isolated toxin, BmajPLA(2)-II, was structurally characterized with MALDI-TOF (Matrix-assisted laser desorption/ionization-time of flight) mass spectrometry, sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), followed by two-dimensional electrophoresis, partial amino acid sequencing, an enzymatic activity assay, circular dichroism, and dynamic light scattering assays. These structural characterization tests presented BmajPLA(2)-II as a basic Lys49 PLA(2) homologue, compatible with other basic snake venom PLA(2)s (svPLA(2)), with a tendency to form aggregations. The in vitro anti-parasitic potential of B. marajoensis venom and of BmajPLA(2)-II was evaluated against Leishmania infantum promastigotes and Trypanosoma cruzi epimastigotes, showing significant activity at a concentration of 100 mu g/mL. The venom and BmajPLA(2)-II presented IC50 of 0.14 +/- 0.08 and 6.41 +/- 0.64 mu g/mL, respectively, against intraerythrocytic forms of Plasmodium falciparum with CC50 cytotoxicity values against HepG2 cells of 43.64 +/- 1 7.94 and >150 mu g/mL, respectively. The biotechnological potential of these substances in relation to leishmaniasis, Chagas disease and malaria should be more deeply investigated.